The major entry pathway of calcium ions (Ca2+) in electrically nonexcitable cells is the store-operated calcium channel (SOC). The store-operated channel is encoded by the Orai gene and is the pore forming subunit of the Ca2+-release activated Ca2+ (CRAC) channel. See Prakriya, M. et al., Nature 443, 230-233 (2006); Vig, M. et al, Curr Biol 16, 2073-2079 (2006); and Yeromin, A. V., et al., Nature 443, 226-229 (2006). When intracellular stores of Ca2+ are low or depleted, then Ca2+ influx through the store-operated calcium channel is activated.
In the context of neuronal activity, calcium ions act as intracellular messengers during synaptic transmission and in developmental processes. Specific attributes of a Ca2+“signature” such as, amplitude, duration and frequency of the signal can determine the morphology of a neural circuit by affecting the outcome of cell migration, the direction taken by a growth-cone, dendritic development and synaptogenesis. See Berridge, M. J., Neuron, 21, 13-26 (1998). Ca2+ signals also determine the nature and strength of neural connections in a circuit by specifying neurotransmitters and receptors. See Borodinsky, L. N. & Spitzer, N. C., Proc Natl Acad Sci USA, 104, 335-340 (2007). Thus, neuronal Ca2+ signals can affect excitability and neural circuit formation.
The inositol 1,4,5-trisphosphate receptor (InsP3R, itpr) gene is a ligand gated Ca2+-channel present on the membranes of intracellular Ca2+ stores. See Banerjee, S. et al., J Neurosci 24, 7869-7878 (2004); Joshi, R. et al., Genetics 166, 225-236 (2004). It is thought to be involved in various aspects of neuronal function including excitability, neurotransmitter release, synaptic plasticity and gene transcription. See Banerjee, S. & Hasan, G., Bioessays, 27, 1035-1047 (2005); Berridge, M. J., Neuron 21, 13-26 (1998). Mutants in the gene coding for the mouse InsP3R1 are ataxic. See Matsumoto, M. et al., Nature 379, 168-171 (1996); Street, V. A. et al., J. Neurosci., 17, 635-645 (1997).